Key words
sitagliptin - basal insulin - insulin secretion capacity
Introduction
Basal insulin preparation is recommended by the American Diabetes Association (ADA)/European
Association for the Study of Diabetes (EASD) consensus algorithm when lifestyle interventions
and oral glucose-lowering agents no longer achieve the glycemic goal of hemoglobin
A1c (HbA1c) level less than 53 mmol/mol [1]
[2]. Recently, 2 long-acting insulin analogues, insulin glargine and insulin detemir,
are available that attain glycemic targets more effectively and safely [3]
[4]. There are no significant differences reported in glycemic control and overall hypoglycemia
between the 2 analogues [5]. The combination of basal insulin and oral hypoglycemic agents (OHAs), known as
basal-supported oral therapy (BOT), is often used to treat poorly controlled type
2 diabetes [6]
[7]. Better glycemic control, fewer hypoglycemic episodes, and less weight gain are
obtained by BOT than by biphasic insulin [8]. In addition, BOT is relatively cost effective with the same glycemic control level
as biphasic insulin regimen [9]. BOT is also helpful in Japanese type 2 diabetes patients. In the ALOHA (Add-on
to Lantus® to OHA) study, in which 5 223 Japanese type 2 diabetes patents participated, mean
HbA1c was reduced from 75±13 to 60±13 mmol/mol in 24 weeks [10]. Although BOT is well-tolerated and effective for glycemic control, patients sometimes
experience nocturnal and early morning hypoglycemia. In the ALOHA study, 0.97% of
the patients experienced frequent hypoglycemia. In the 4 T-study, 1.3% of BOT-treated
patients experienced hypoglycemia with loss of consciousness [8]. Another problem of BOT is that postprandial glucose is high, although morning fasting
blood glucose level is within normal range. An increase in dosage of basal insulin
or sulfonyl ureas (SUs); which are most commonly administrated in BOT-treated Japanese
patients, is not always effective, and can result in increased hypoglycemia. In Japanese
interview forms, frequency of hypoglycemia induced by SUs is reported to be 1.3–2.8%.
Thus, maintaining targeted glycemic control by BOT is limited in some patients.
Dipeptidyl peptidase-4 (DDP-4) inhibitor is a newly developed OHA that prevents degradation
of the incretin hormones, glucagon-like peptide-1, and gastric inhibitory polypeptide
[11]. This compound stimulates glucose-dependent insulin secretion and suppresses glucagon
release, and can improve both fasting and postprandial glucose levels. Four different
DPP-4 inhibitors are available in Japan: sitagliptin, vildagliptin, alogliptin, and
linagliptin. Of these, sitagliptin is most widely used, partly because it was the
first approved DPP-4 inhibitor and the safety and efficacy are acceptable in Japanese
clinical practice. Generally, sitagliptin is more effective for glycemic control in
Japanese patients compared to Caucasian patients [12]
[13]. Sitaglipitn is usually combined with low dosage of SUs in Japan, less than or equal
to 2 mg/day of glimepiride and 40 mg/day of gliclazide, which is enough for glycemic
control when combined with sitagliptin [14]. Patients also show improved glycemic control even if insulin secretion capacity
is insufficient for oral therapy [14]
[15]. The main pathophysiology of Japanese type 2 diabetes is impairment of insulin secretion
[16]
[17]. Insulin secretion capacity in Japanese populations is only about half of that in
Caucasians [18]. Both decreased basal and early phase insulin secretion contribute more to Japanese
type 2 diabetes [16], and insulin therapy is usually required in those with C-peptide index (CPI) lower
than 0.8 [19]. However, basal insulin therapy is not always ideal in some patients because postprandial glucose
is still high and preprandial glucose is low, which results in large fluctuations in blood glucose. On the other hand, DPP-4 inhibitor might nevertheless ameliorate
decreased early phase insulin secretion. This encouraged us to consider whether basal
insulin can be replaced with sitagliptin in type 2 diabetes patients treated with
SUs and basal insulin in at least some BOT cases.
We show here that sitagliptin can be switched from basal insulin in patients with
C-peptide index (CPI) and/or secretory unit of islet in transplantation (SUIT) equal
to or larger than 1.19 and/or 36.4, respectively, with beneficial effects on glycemic
control.
Materials and Methods
Study design and participants
This was a prospective, 52-week, single center, and single arm intervention study
to evaluate the effects on glycemic control of replacement of basal insulin to sitagliptin
in type 2 diabetes patients inadequately controlled with BOT. Outpatients of Takashima
General Hospital were recruited consecutively for a sample size of 45 subjects. Inclusion
criteria were: type 2 diabetes treated with basal insulin (insulin glargine or detemir)
and SUs (glimepiride or gliclazide)±metformin±thiazolidinedione±α-glucosidase inhibitors
for more than 1 year; aged ≥20 years; HbA1c level ≥52 mmol/mol; no improvement in
HbA1c ≥5 mmol/mol within 3 months in BOT; and a fasting C-peptide reactin (CPR) of
>0.5 ng/ml. Exclusion criteria were: type 1 diabetes; secondary diabetes; alcoholism;
severe depression, or severe psychological condition; malignancy; and abnormal hemoglobinemia.
The study protocol was approved by the Institutional Review Board of Takashima General
Hospital, and registered at the University hospital Medical Information Network in
Japan (UMIN000005499). Written informed consent was obtained from all subjects.
Procedures and intervention
The duration of the study was 52 weeks. Subjects were screened for eligibility and
gave basic demographic information, medical history, and frequency of hypoglycemia.
Within a month before changing therapy from basal insulin to sitagliptin, glucagon
loading test was performed without any OHAs or basal insulin for more than 24 h to
evaluate insulin secretion capacity. When basal insulin was replaced by sitagliptin,
the dosage of glimepiride or gliclazide was decreased to equal to or less than 2.0 mg/day
or 40 mg/day, respectively, to prevent increased hypoglycemia if the subjects had
been treated with more than 2.0 mg/day glimepiride or 40 mg/day gliclazide. If the
subjects had been treated with equal to or less than 2.0 mg/day of glimepride or 40 mg/day
of gliclazide, that dosage of SUs was maintained. Metformin (Met) and thiazolidinedione
(TZD) were continued without any changes during the study. α-Glucosidase inhibitors
were discontinued. The dosage of SUs was changed depending on the frequency of hypoglycemic
episodes and glycemic control level. Sitagliptin was started at 50 mg/day, the usual
initial dosage in Japan, which was increased to 100 mg/day if the HbA1c level did
not reach 52 mmol/mol, since titration to 100 mg/day is acceptable.
Measurements
The primary endpoint was the change in HbA1c in 52 weeks. The secondary endpoints
were dropout rate due to lesser efficacy of replacement by sitagliptin of basal insulin
on glycemic control, change in body weight in 52 weeks, change in body mass index
(BMI) in 52 weeks, change in frequency of hypoglycemia in 52 weeks, adverse events,
and the correlation between change in HbA1c at the 8th week and insulin secretion capacity or CPI or SUIT at baseline. HbA1c are expressed
in mmol/mol according to the recommendation of IFCC. CPI was calculated by the formula:
[100×fasting CPR (ng/ml)]/[18×FPG (mM)] [19]. SUIT index was calculated by the formula: [250×fasting CPR (nM)]/[(FPG − 3.43)
(mM)] [20]. Blood glucose and C-peptide level were measured before (0 min) and 6 min after
intravenous administration of 1 mg glucagon.
Statistical analysis
Sample size was estimated to be 34 to detect a 4 mmol/mol change in HbA1c in 52 weeks
with a power of 95%, alpha 0.05 2-tailed, beta 0.20, standardized effect size 0.7.
To take the dropout rate of 30% into account, the aim was to include 45 subjects.
IBM SPSS Statistics was used for analysis. Dependent samples Student’s t-test was used to compare the means of HbA1c level, insulin secretion capacity, BMI,
body weight, age, and diabetes duration of the subjects between baseline and 52th week. Person’s product-moment correlation test was used to evaluate the relationship
between change in HbA1c and insulin secretion capacity or CPI or SUIT. To evaluate
cutoff values of diabetes duration, FPG, HbA1c, 0-min CPR, 6-min CPR, delta-CPR, CPI,
SUIT, and receiver operating characteristics curve (ROC) analysis were used. Independent
sample Student’s t-test was used to compare the mean of change in HbA1c in 52 weeks between subjects
treated with sitagliptin+glimepiride and sitagliptin+gliclazide. Dunnett analysis
was used to compare change in HbA1c in 52 weeks among subjects treated with sitagliptin+SUs
and sitagliptin+SUs+MET and sitagliptin+SUs+TZD. A p-value of <0.05 was considered
as statistically significant.
Results
Participants
Forty-nine patients were eligible and were consecutively enrolled in the study ([Table 1]). Average age of subjects was 70.0±10.2 years; ratio of male was 60.8%; duration
of diabetes was 14.3±8.2 years; average body weight was 62.3±10.4 kg; average BMI
was 24.3±3.8 kg/m2; and HbA1c was 64±9 mmol/mol. All subjects were treated with SUs; 17 subjects (34.7%)
were treated with glimepiride (average dose 1.67±1.47 mg) and 32 (65.3%) were treated
with gliclazide (average dose 33.8±12.0 mg). Average dosage of basal insulin analogues
was 15.0±8.4 units. Glucagon loading test showed that 0-min CPR, 6-min CPR, CPI, and
SUIT were 1.65±1.02 ng/ml, 3.37±1.98 ng/ml, 1.19±0.64, and 36.5±22.1, respectively.
Sixteen subjects (32.6%) were dropped due to an increase in HbA1c in 8th week; 6 (29.4%) and 11 (34.4%) were dropped in glimepiride- and gliclizaide-treated
subjects, respectively ([Table 2]). No subjects were dropped for other reasons. Thirty-three subjects completed the
study.
Table 1 Demographic and clinical features of subjects participating in the study.
|
Subjects (n)
|
49
|
Basal insulin
|
15.0±8.4 Units
|
|
|
Age (years)
|
70.0±10.2
|
Medications
|
SU 100%
Glimepiride 34.7%
1.67±1.47 mg
Gliclazide 65.3%
33.8±12.0 mg
|
|
Male
|
60.8%
|
|
|
|
Diabetes duration (years)
|
14.3±8.2
|
|
Metformin 22.4%
636±131 mg
|
|
Complications
|
Nephropathy
61.2%
|
|
Thiazolidinedione 16.3%
10.3±3.9 mg
|
|
Retinopathy
69.4%
|
|
α-Glucosidase inhibitors
8.1%
|
|
Neuropathy
42.8%
|
Glucagon test
0-min CPR (ng/ml)
|
1.65±1.02
|
|
Cardiovascular diseases 34.7%
|
6-min CPR (ng/ml)
|
3.37±1.98
|
|
Weight (kg)
|
62.3±10.4
|
Delta CPR (ng/ml)
|
1.72±1.23
|
|
BMI (kg/m2)
|
24.3±3.8
|
CPI
|
1.19±0.64
|
|
HbA1c (mmol/mol)
|
64±8
|
SUIT
|
36.5±22.1
|
Table 2 Changes in HbA1c, and dosages of SUs and sitagliptin in final subjects.
|
Subjects (n)
|
Dropout rate (%) (n)
|
HbA1c level baseline (mmol/mol)
|
HbA1c level 52nd week (%)
|
Change in HbA1c (mmol/mol) (95% CI)
|
Original dosage of SUs (mg)
|
Initial dosage of SUs (mg)
|
Final dosage of SUs (mg)
|
Final dosage of sitagliptin (mg)
|
|
*p<0.05, **p<0.01
|
|
Final
33
|
32.6%
16
|
61±7
|
57±7**
|
− 4*
( − 5 to − 4)
|
–
|
–
|
–
|
74.2±25.4
|
|
Glimepiride
12
|
29.4%
5
|
63±9
|
55±9**
|
− 8*
( − 11 to − 5)
|
1.58±0.93
|
0.96±0.40*
|
1.42±0.57*
|
70.8±25.7
|
|
Gliclazide
21
|
34.4%
11
|
60±6
|
58±7*
|
− 2*
( − 4 to − 0)
|
38.2±14.0
|
24.8±8.7*
|
31.4±12.0*
|
77.3±25.5
|
|
SUs
23
|
30.3%
10
|
60±7
|
56±7*
|
− 4*
( − 6 to − 2)
|
–
|
–
|
–
|
67.4±24.3
|
|
SUs+Met
7
|
36.4%
4
|
64±9
|
58±8
|
− 6*
( − 10 to − 2)
|
–
|
–
|
–
|
87.5±23.1
|
|
SUs+TZD
3
|
62.5%
5
|
65±6
|
63±5
|
− 2*
( − 5 to − 0)
|
–
|
–
|
–
|
100±0.0
|
HbA1c findings and dosage of SUs and sitagliptin
Therapy adherence was confirmed by certified diabetes educators (nurses) in the study.
Adherence of BOT therapy and the switching therapy were almost 100% for both therapies
(data not shown).
HbA1c level in 52 weeks in final subjects was significantly decreased from 61±8 to
57±8 mmol/mol (p<0.01) ([Table 2]). Change in HbA1c in 52 weeks was − 4 mmol/mol (95% CI; − 5 to − 4 mmol/mol)
(p<0.05). HbA1c levels in 52 weeks in glimepiride-treated subjects (n=12) were significantly
decreased from 63±9 mmol/mol to 55±9 mmol/mol (p<0.01). Change in HbA1c in 52 weeks
was − 8 mmol/mol (95% CI; − 11 to − 5 mmol/mol) (p<0.05). HbA1c levels in 52 weeks
in gliclazide-treated subjects (n=21) were significantly decreased from 54±6 to 58±7 mmol/mol
(p<0.05). Change in HbA1c in 52 weeks was − 2 mmol/mol (95% CI; − 4 to − 0 mmol/mol)
(p<0.05). There was a significant difference in change in HbA1c in 52 weeks between
glimepride-treated and gliclazide-treated subjects (p<0.01). The original dosages
of glimepiride and gliclazide before the study were 1.58±0.93 mg/day and 38.2±14.0 mg/day,
respectively; the initial dosages at the beginning of the study were significantly
decreased to 0.96±0.40 mg/day and 24.8±8.7 mg/day, respectively (p<0.05); and the
final dosages were significantly increased to 1.42±0.57 mg/day and 31.4±12.0 mg/day,
respectively, compared to the initial dosages (p<0.05), and were almost equal to the
original dosages ([Table 2]). Final dosage of sitagliptin was 74.2±25.4 mg/day in all subjects; 70.8±25.7 mg/day
in glimepiride-treated subjects; and 77.3±25.5 mg/day in gliclazide-treated subjects
with no significant difference between the 2 groups.
Of 33 subjects who completed the study, 22 subjects were treated with sitagliptin
and SUs, 6 subjects were treated with sitagliptin and SUs and MET, and 3 subjects
were treated with sitagliptin and SUs and TZD; changes in HbA1c in 52 weeks were − 4 mmol/mol
(95% CI; − 6 to − 2 mmol/mol) (p<0.05), − 6 mmol/mol (95% CI; − 10 to − 2 mmol/mol)
(p<0.05), and − 3 mmol/mol (95% CI; − 0.5 to − 0 mmol/mol) (p<0.05), respectively
([Table 2]). However, there was no significant difference among the 3 groups.
Change in body weight, BMI, and frequency of hypoglycemia
Body weight in final subjects at baseline was 64.2±9.5 kg, and was decreased to 63.5±8.7 kg
at 52nd week. Change in body weight in 52 weeks was − 0.71 kg (95% CI; − 1.42 to − 0.004 kg)
(p<0.05) ([Table 3]). BMI at baseline was 24.8±3.6 kg/m2, and decreased to 24.5±3.4 kg/m2 at 52nd week. Change in BMI in 52 weeks was − 0.27 kg/m2 (95% CI; − 0.54 to 0.004 kg/m2) (p>0.05).
Table 3 Changes in weight, BMI, and frequency in hypoglycemia.
|
Weight (kg)
|
BMI (kg/m2)
|
Hypoglycemia (times/month)
|
|
*p<0.05, ***p<0.001
|
|
0-week
|
64.2±9.5
|
24.8±3.6
|
1.21±1.05
|
|
52nd week
|
63.5±8.7
|
24.5±3.4
|
0.06±0.24***
|
|
Change
(95% CI)
|
− 0.71*
( − 1.42 to − 0.004)
|
− 0.27
( − 0.54 to 0.004)
|
− 1.21*
( − 1.5 to − 0.80)
|
Frequency of hypoglycemia at baseline was 1.21±1.05 times/month, and was significantly
decreased to 0.06±0.24 times/month at 52nd week (p<0.001). Change in frequency in hypoglycemia in 52 weeks was − 1.21 times/months
(95% CI; − 1.5 to − 0.80 times/month) (p<0.05) ([Table 3]). During the study, no severe hypoglycemia was noted. During the study, no other
adverse events were observed after replacement of basal insulin with sitagliptin.
Differences in HbA1c findings in 8-week in the final and dropped subjects
Sixteen of 49 subjects recruited dropped out after 8 weeks due to increased HbA1c
level. The remaining 33 subjects completed the study. HbA1c level at baseline (0-week)
in final subjects was 61±8 mmol/mol, and was significantly decreased to 58±7 mmol/mol
at 8th week (p<0.001) ([Table 4]). Change in HbA1c was − 4 mmol/mol (95% CI; − 5 to − 2 mmol/mol) (p<0.05). On
the other hand, HbA1c level at baseline (0-week) in dropped subjects was significantly
higher than that in final subjects (p<0.05), and was significantly increased from
69±9 to 73±11 mmol/mol in 8 weeks (p<0.01). Change in HbA1c was +7 mmol/mol (95% CI;
0.3 to 11 mmol/mol) (p<0.05).
Table 4 Changes in HbA1c and background of final and dropped subjects.
|
Final subjects
33
|
Dropped subjects
16
|
|
Final subjects
33
|
Dropped subjects
16
|
|
*p<0.05, **p<0.01, ***p<0.001
|
|
0 Wk HbA1c (mmol/mol)
|
61±7
|
69±10
|
Original dosage
of SUs (mg)
|
Glimepiride
1.58±0.93
Gliclazide
36.2±10.2
|
Glimepiride
2.70±2.05
Gliclazide
38.2±14.1
|
|
8 Wk HbA1c (mmol/mol)
|
58±7***
|
73±10**
|
Basal insulin (Units)
|
14.8±9.3
|
15.2±6.4
|
|
Delta HbA1c (mmol/mol)
(95% CI)
|
− 4*
( − 5 to − 2)
|
7*
(0.3 to 11)
|
FPG (mM)
|
7.4±1.5
|
8.9±2.9*
|
|
Age (years)
|
69.8±10.7
|
70.5±9.3
|
HbA1c (mmol/mol)
|
61±7
|
69±10**
|
|
Male (%)
|
66.7
|
56.3
|
Glucagon test
0-min CPR (ng/ml)
|
1.95±1.25
|
1.37±0.64*
|
|
Diabetes duration (years)
|
12.1±6.6
|
18.7±9.5*
|
6-min CPR (ng/ml)
|
3.81±2.13
|
2.42±1.21*
|
|
Weight (kg)
|
64.2±9.5
|
58.4±11.5
|
Delta CPR (ng/ml)
|
1.98±1.35
|
1.16±0.69*
|
|
BMI (kg/m2)
|
24.8±3.6
|
23.4±4.0
|
CPI
|
1.35±0.68
|
0.92±0.51*
|
|
|
|
SUIT
|
42.7±23.0
|
23.1±10.6**
|
Differences in clinical factors in final and dropped subjects
There were no differences in age, sex, dosage of SUs, or dosage of basal insulin in
final and dropped subjects ([Table 4]). Body weight and BMI also were not significantly different (p=0.065 and p=0.2432, respectively). On the other hand, diabetes duration in dropped subjects was
longer than that in final subjects (12.1±6.6 vs. 18.7±9.5 years, p<0.05). FPG and
HbA1c also were higher in dropped subjects than in final subjects (FPG; 7.4±1.5 vs.
8.9±2.9 mM, p<0.05) (HbA1c; 61±7 vs. 69±9 mmol/mol, p<0.01).
Insulin secretion capacity was significantly higher in final subjects than that in
dropped subjects ([Table 4]) (p<0.05). In final subjects, CPR level at 0-min, 6-min, and delta CPR (6-min CPR
to 0-min CPR) were 1.95±1.25 ng/ml, 3.81±2.13 ng/ml, and 1.98±1.35 ng/ml, respectively.
In dropped subjects, CPR level at 0-min, 6-min, and delta CPR were 1.37±0.64 ng/ml,
2.42±1.21 ng/ml, and 1.16±0.69 ng/ml, respectively. CPI and SUIT index also were significantly
higher in final subjects than those in dropped subjects. CPI at baseline in final
subjects was 1.35±0.68, while that in dropped subjects was 0.92±0.51 (p<0.05). SUIT
at baseline was 42.7±23.0 in final subjects, and 23.1±10.6 in dropped subjects (p<0.01).
We examined cutoff values of diabetes duration, FPG, HbA1c, 0-min CPR, 6-min CPR,
delta-CPR, CPI, and SUIT by analyzing ROC curves; they were 16.5 years, 8.2 mM, 62 mmol/mol,
1.25 ng/ml, 2.80 ng/ml, 1.60 ng/ml, 1.34, and 37.5, respectively ([Fig. 1]).This indicates that with longer diabetes duration, insulin secretion capacity becomes
lower and the consequent poorer glycemic control makes switching BOT-treated patients
from basal insulin to sitagliptin unsafe.
Fig. 1 Cutoff values and receiver-operator characteristic curves of a diabetes duration, b fasting plasma glucose, c HbA1c, d 0-min CPR, e 6-min CPR, f delta CPR, g CPI, and h SUIT at baseline. CPR: C-peptide reaction; CPI: C-peptide index; SUIT: the secretory
unit of islet in transplantation.
Correlation between efficacy of sitagliptin on glycemic control and insulin secretion
capacity, CPI, and SUIT
We examined whether or not insulin secretion capacity, CPI, or SUIT at baseline predicted
the efficacy of replacing basal insulin with sitagliptin on glycemic control ([Fig. 2]). There was a correlation between change in HbA1c at 8th week and 0-min CPR (r= − 0.281), 6-min CPR (r= − 0.326), and delta CPR (r= − 0.290),
assessed by glucagon loading test at baseline ([Fig. 2a, b, c]) (p<0.05). In addition, CPI (r= − 0.360) or SUIT (r= − 0.306) at baseline was correlated
with change in HbA1c at 8th week ([Fig. 2d, e]) (p<0.05). The value of 0-min CPR, 6-min CPR, delta CPR, CPI, and SUIT at which
the HbA1c level was not increased by replacement of basal insulin by sitagliptin were
calculated to be 1.64 ng/ml, 3.36 ng/ml, 1.71 ng/ml, 1.19, and 36.4, respectively,
by Pearson’s product-moment correlation test ([Table 5]). The value of 0-min CPR, 6-min CPR, delta CPR, CPI, and SUIT at which the HbA1c
level was decreased by 0.5% in 8 weeks were calculated to be 1.86 ng/ml, 3.83 ng/ml,
1.98 ng/ml, 1.36, and 41.3, respectively. Other clinical characteristics of the patients
such as disease duration and body weight were not significantly correlated with efficacy
of replacing basal insulin with sitagliptin on glycemic control (data not shown).
Fig. 2 Relationship between changes in HbA1c in 8 weeks and results of glucagon loading
test, CPI, and SUIT at baseline. Changes in HbA1c in 8 weeks and 0-min CPR a, 6-min CPR b, delta CPR c, CPI d, and SUIT index e at baseline. CPR: C-peptide reaction; CPI: C-peptide index; SUIT: the secretory unit
of islet in transplantation. *p<0.05.
Table 5 Correlation between change in HbA1c and insulin secretion capacity.
|
Change in HbA1c (mmol)
|
0-Minute CPR
(ng/ml)
|
6-Minute CPR
(ng/ml)
|
Delta CPR
(ng/ml)
|
CPI
|
SUIT
|
|
0.0
|
1.64
|
3.36
|
1.71
|
1.19
|
36.4
|
|
− 5
|
1.86
|
3.83
|
1.98
|
1.36
|
41.3
|
Discussion
We show here that basal insulin can be switched to sitagliptin with good effects in
type 2 diabetes patients treated with BOT. With this treatment, the HbA1c level decreased
from 61±7 to 57±7 mmol/mol in 52-week (p<0.01). The change in HbA1c in 52 weeks was
− 4 mmol/mol (95% CI; − 5 to − 4 mmol/mol) (p<0.05). The efficacy of switching
to sitagliptin from basal insulin was correlated with insulin secretion capacity,
CPI, and SUIT; CPI being most correlated marker in the present study. The average
CPI in final subjects was 1.35±0.68 ng/ml, while that of dropped subjects was 0.92±0.51 ng/ml.
Pearson’s product-moment correlation test revealed that HbA1c was improved by switching
from basal insulin to sitagliptin if CPI was equal to or higher than 1.19 ([Fig. 2d] and [Table 5]). Similarly, basal insulin could be switched to sitagliptin if SUIT was equal to
or larger than 36.4 ([Fig. 2e] and [Table 5]). In the dropped subjects, diabetes duration was longer, FPG and HbA1c were worse,
0-min CPR, 6-min CPR, delta-CPR, CPI, and SUIT were lower compared to those in final
subjects ([Table 4]). Cutoff values were 16.5 years, 8.2 mM, 62 mmol/mol, 1.25 ng/ml, 2.80 ng/ml, 1.60 ng/ml,
1.34, and 37.5, respectively ([Fig. 1]). This suggests that the efficacy of switching from basal insulin to sitagliptin,
when combined with SUs, is dependent on basal glycemic control and the insulin secretion
capacity. Baseline HbA1c of dropped subjects was higher than that of the final subjects.
A higher dosage of basal insulin was required to reach target HbA1c level in dropped
subjects compared to that in final subjects because of lower insulin secretion capacity.
Thus, if baseline HbA1c level were reduced by increasing the dosage of basal insulin,
it would be difficult to replace basal insulin with sitagliptin.
Replacement of basal insulin by sitagliptin resulted in a reduction in body weight
and hypoglycemia. Body weight was reduced by 0.71 kg (95% CI; − 1.41 to − 0.004 kg)
(p<0.05). Frequency of hypoglycemia was decreased from 1.21±1.05 to 0.06±0.24 times/month
(p<0.001). Since sitagliptin is known to be body weight neutral [21]
[22], discontinuation of basal insulin might contribute to body weight reduction. The
combination of basal insulin and SUs often induces mild hypoglycemia by which patients
feel a sense of hunger and eat between-meal snacks. This sometimes induces weight
gain and poor glycemic control in BOT-treated patients. On the other hand, combination
therapy with sitagliptin and low dosage SUs (less than or equal to 2 mg/day glimepiride
or 40 mg/day gliclazide) was body weight neutral or led to a decrease in BMI [14]. In the current study, hypoglycemia seldom occurred, and BMI was significantly decreased
by 0.38 kg/m2 (95% CI − 0.72 to − 0.04 kg/m2) [14]. Switching from basal insulin to sitagliptin also reduced the frequency of hypoglycemia.
Although energy intake was not evaluated between baseline and 52-week in the present
study, patients who had previously experienced frequent hypoglycemia reported to their
physicians that the number of between-meal snacks in 52 weeks was fewer than at baseline.
Thus, excess energy intake may be reduced after switching from basal insulin to sitagliptin
to account for some of the body weight reduction and improvement in HbA1c. Another
reason for improvement in the HbA1c level may be the reduced postprandial glucose
level by the combination therapy with sitagliptin and SUs compared to that by BOT.
The combination therapy of glimepiride and sitagliptin was more effective for HbA1c
reduction than that of gliclazide and sitagliptin. Recently, it was reported that
cAMP sensor Epac2 is a direct target of several sulfonylureas [23]. Tolbutamide, glibenclimide, and glimepiride bound Epac2 and enhanced glucose-stimulated
insulin secretion. However, gliclazide did not bind Epac2. Because Epac2 also mediates
the potentiation of insulin secretion by cAMP increased by endogenous incretin, the
combination therapy of glimepiride and sitagliptin enhances more insulin secretion
through activation of Epac2. This might be a potential mechanism why the combination
therapy of glimepiride and sitagliptin was more effective for glycemic control than
that of gliclazide and sitagliptin.
Generally, insulin secretion capacity of Japanese is as half as that of Caucasian
[16]
[17]
[18]. Therefore, more than 60% of Japanese type 2 diabetes patients are treated with
SUs [24]. DPP-4 inhibitor now is one of the most popular OADs, and more than 2 million patients
were treated with DPP-4 inhibitors in Japan. Based on pathophysiology of Japanese
patients and the mechanism of incretin effect, the combination therapy with SUs and
DPP-4 inhibitors seems to be most effective for glycemic control compared to that
with other OADs and DPP-4 inhibitors. On the other hand, the main pathophysiology
of Caucasian type 2 diabetes is insulin resistance compared to that of Japanese type
2 diabetes [25]
[26]. Dosage of basal insulin in BOT in Caucasian patients is greater than that in Japanese
patients. For example, in 4-T study, the mean dosage of basal insulin was 86 U (1.03 U/kg)
[8], while 8.5 U (0.15 U/kg) in Japanese type 2 diabetes [10], and 15 U (0.24 U/kg) in our study. Therefore, it is not sure if basal insulin could
be replaced with DPP-4 inhibitors even in subjects treated with high dosage of basal
insulin. However, there is still a possibility that in Caucasian subjects whose BMI
is less than 25 kg/m2 and CPI is over 1.3, basal insulin could be replaced with DPP-4 inhibitors. Or, if
the combination therapy with high dosage of MET and DPP-4 inhibitors is more effective
for glycemic control compared to other combinations in Caucasian type 2 diabetes,
basal insulin with MET could be replaced with DPP-4 inhibitors and metformin.
During the course of the disease, type 2 diabetes patients are treated with several
OHAs [27]
[28]. However, if the HbA1c level does not reach less than 53 mmol/mol, insulin treatment
is considered the next step [1]
[2]. BOT is often selected for outpatients because once daily injection is acceptable
and the glycemic control is superior, with fewer hypoglycemic episodes and less weight
gain compared to biphasic insulin [8]. In Japan, the commonly used SUs are combined with basal insulin in BOT [10]. One of the biggest problems of combination therapy with basal insulin and SUs is
the high level of postprandial blood glucose while fasting blood glucose is within
normal range. An increase in dosage of SUs or basal insulin does not resolve this
problem, and sometimes leads to increased hypoglycemia. However, our results show that better glycemic control and lower frequency of hypoglycemia
is obtained when switching from basal insulin to sitagliptin in subjects with sufficiently
preserved insulin secretion capacity.
The advantages of discontinuation of basal insulin are 1) patients become free from
daily injections; 2) they do not need to regularly perform self-monitoring of blood
glucose (SMBG); and 3) oral therapy costs less than insulin therapy.
In summary, basal insulin in BOT can be switched to sitagliptin if CPI and/or SUIT
are equal to or higher than 1.19 or 36.4, respectively. On the other hand, sitagliptin
can be added to insulin therapy if insulin secretion capacity is not sufficient for
switching to sitagliptin. However, the effectiveness of combination therapy with basal
insulin and sitagliptin on glycemic control in type 2 patients with CPI and/or SUIT
less than 1.19 or 36.4, respectively, is unknown. Further studies are required to
determine the optimum insulin secretion capacities for switching BOT therapy to sitagliptin
combined with SUs or combination therapy with sitagliptin and basal insulin or GLP-1
receptor analogues.
